Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies.
CD20 is a nonglycosylated 33 to 37 kD phosphoprotein involved in B-cell signaling that subserves important functions in the regulation of B-cell proliferation and differentiation. In addition, this B-cell surface antigen has been shown recently to be an effective target for immunotherapy of B-cell malignancies using chimeric (mouse/human) or radiolabeled murine monoclonal anti-CD20 antibodies. In this report we show that extensive crosslinking of CD20 with murine anti-CD20 monoclonal antibodies (MoAbs) in the presence of either goat anti-mouse IgG or Fc receptor (FcR)-expressing cells directly inhibits B-cell proliferation, induces nuclear DNA fragmentation, and leads to cell death by apoptosis. The apoptotic effects of these MoAbs can be inhibited by chelation of extracellular or intracellular Ca2+ by EGTA or Bapta AM, indicating that anti-CD20-mediated apoptosis may be related to changes in Ca2+ concentration. These findings suggest that ligation of CD20 in vivo by anti-CD20 antibodies in the presence of FcR-expressing cells may initiate signal transduction events that induce elevation of [Ca2+]i and lead to apoptosis of malignant B cells, thereby contributing to the impressive tumor regressions observed in mouse models and clinical trials using anti-CD20 MoAbs.
Shan
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Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
Ledbetter
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Press
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D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology / Q000502:physiology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D002051:Burkitt Lymphoma / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D002614:Chelating Agents / Q000494:pharmacology; D003432:Cross-Linking Reagents; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006041:Goats; D006801:Humans; D051379:Mice; D011961:Receptors, Fc / Q000502:physiology; D014407:Tumor Cells, Cultured
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D002614:Chelating Agents; D003432:Cross-Linking Reagents; D011961:Receptors, Fc; D004533:Egtazic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium